1. Field of the Invention
The present invention relates to a surgical cement, also known as bone cement or bioresorbable implantation, and more particularly to a surgical calcium phosphate citrate-containing cement that is bioresorbable and bioactive for orthopedic, dental, and maxillofacial applications and a manufacturing method thereof.
2. Description of Related Art
The major inorganic constitution of hard tissues is biological apatite. Hydroxyapatite (HA) is a calcium phosphate compound which has same crystal structure as the biological apatite. In principle, HA should be an ideal candidate as a hard tissue replacement material. However, the precipitated HA has a very fine particle size. Because of manipulation requirement, this hinders the applications of precipitated HA in the medical area.
Many types of calcium phosphate ceramics have been prepared by a high temperature sintering technique, and have been approved as useful and biocompatible materials for bone substitutes. These include tetracalcium phosphate (TTCP), HA, alpha-tricalcium phosphate (α-TCP) and beta-tricalcium phosphate (β-TCP), calcium pyrophosphate, and biphasic calcium phosphate (BPC) ceramics. Most of the calcium phosphate ceramics for medical application are prepared either as a granular form or block form. The granular form has a mobility problem while the block form is very brittle and is difficult to shape. In order to solve the above problem, many attempts have been made to prepare bioresorbable grouts or cement materials as binder for the granule form of the calcium phosphate ceramics. Among these are Plaster of Paris, collagen, polymers and several types of calcium phosphate cements.
Chow and his coworkers (U.S. Pat. Nos. 4,518,430 and 4,612,053) started the development of calcium phosphate cement about twenty-five years ago. The first calcium phosphate cement is based on the interaction of TTCP and dicalcium phosphate (DCP) to form hardened cement with a final product which is HA. After that, many modifications on the HA cement have been made by adding setting time regulators or other reagents to improve the flow character. However, the HA cement is resorbed very slowly and does not set well in a wet environment. Beside, its flow character is poor. Another type of calcium phosphate cement developed is dicalcium phosphate dihydrate (DCPD). The basic constitution of this type of cement is a basic calcium phosphate compound having a Ca/P mole ratio greater than 1 with monocalcium phosphate monohydrate, monocalcium phosphate anhydrous or phosphoric acid. The common basic calcium phosphate compounds used are tricalcium phosphate (TCP) and HA. Sometimes, calcium oxide or calcium carbonate can also be used. Disadvantages of this type of cement are very acidic at the time of setting, poor flow, and weak mechanical strength and difficult to get a consistent result. Therefore, this type of cement normally keeps the basic components in excess. After setting, there are some unreacted components together with the reaction product, DCPD. This type of cement also does not set well in a liquid environment.
The majorities of calcium phosphate (CP) cements are either HA cement or DCP cement. Both types of cements use calcium phosphate compounds only, one with a higher Ca/P mole ratio while the other with a lower Ca/P mole ratio. The most common compounds with high Ca/P mole ratios are TTCP, HA and TCP. In the past, some attempts have been made by using these calcium phosphate compounds having high Ca/P ratios as cementing components, and using other soluble non-calcium phosphate containing acidic compounds as setting reagents. These acidic compounds include phosphoric acid, bi-functional organic acids, citric acid and polycyclic acid. These cements are normally very acidic in nature and take a very long time to reach a neutral pH. After implantation, these cements would cause irritation and inflammatory reactions. Beside, these cements are difficult to control bioresorpion and do not have a good manipulation character. Other bone cement utilizes soluble alkaline silicate as a setting solution. The reaction product is calcium silicate.
A resorbable bioactive calcium phosphate cement was proposed by S. T. Liu et al. in U.S. Pat. No. 5,149,368, comprising a cementing powder of TTCP, a setting reagent consisting of an acidic citrate salt, and sufficient water to form a cementitious paste. S. T. Liu et al. further proposed a resorbable bioactive phosphate containing cement in U.S. Pat. No. 5,262,166, in which this surgical cement comprises a cementing powder consisting of calcium sodium phosphate or calcium potassium phosphate ceramics, a setting reagent consisting of citric acid or acidic citrate salts, and water. In both the patents, the acidic citrate salt is selected from the group consisting of soluble NaH2 citrate, Na2H citrate, KH2 citrate, K2H citrate, NH4H2 citrate, and (NH4)2H citrate.
However, using soluble citric acid or soluble acidic citrate, such as NaH2 citrate, Na2H citrate, KH2 citrate, K2H citrate, NH4H2 citrate, and (NH4)2H citrate, as the setting reagent, the setting time is very sensitive to the used amount of the acidic setting reagent. The solubility of calcium phosphate compounds depends strongly on the pH of the solution. At pH around 7, the solubility of calcium phosphate compounds follow the order TTCP>α-TCP>β-TCP>HA. The decomposed HA which contains both TTCP and α-TCP should also have higher solubility than β-TCP and HA. By reacting the calcium phosphate compound, having a Ca/P mole ratio equal to 1.5 or higher, with citric aid, it will produce calcium ions, phosphate ions and citrate ions to form other calcium phosphate compounds and corresponding calcium citrate, such as monocalcium citrate (Ca(H2 Citrate)2), dicalcium citrate (CaH Citrate), tricalcium citrate (Ca3 Citrate2) or a calcium phosphate citrate complex depending on the pH of the solution. Whether the calcium phosphate compound can form setting cement with citric aid or not strongly depends on the nature of calcium phosphate compounds. For example, TTCP, α-TCP, or decomposed HA which has high solubility and a high dissolution rate is able to form cement with citric acid in a relatively short time, within 15 minutes. Nevertheless, it is essential precondition that a ratio of the calcium phosphate to citric acid should stays relatively high, normally higher than 3. The more the amount of citric acid, the cement has longer setting time and is more acidic. If the ratio is near 3 or lower, the mixture paste does not set within one hour. Thus, the suitable amount of citric acid for setting stays in a rather narrow range. For the β-TCP or HA, because of their low dissolution rate, it can form paste with citric acid, but will not set and become hardened at all.
Ideally, a useful cementing material for hard tissue application should have good biocompatibility, a suitable bioresorption rate, and a good setting character with a reasonable setting time. Most of the above cements have certain disadvantages.